1. Field of the Invention
The invention relates to a process for enantioselectively producing a chiral carboxylic acid from a racemic precursor which is at the oxidation level of an aldehyde. The conversion of the precursor to the chiral carboxylic acid is accomplished by exposing the precursor to a microorganism or an enzyme preparation derived from a microorganism.
2. Information Disclosure
The oxidation of aldehydes to carboxylic acids is a classic manipulation of organic chemistry. However, typical chemical oxidants provide no selectivity among possible enantiomeric products when the starting material is racemic. It is known in other reactions that when an enzyme can be employed to carry out a conversion, it is sometimes found that the conversion is enantioselective. Thus, for example, Patterson et al. [J. Org. Chem. 46, 4682-4685 (1981)] describe the enzymatic conversion of .alpha.-ketoaldehydes to optically active .alpha.-hydroxyacids using glyoxalase I and glyoxalase II. The inventors are aware of no examples of the enantioselective conversion of racemic aldehydes to chiral carboxylic acids using microorganisms or enzymes therefrom.
The enantioselective conversion of racemic aldehydes to chiral acids would be a particularly useful process in the pharmaceutical industry, especially for the synthesis of single enantiomers of chiral acids of the NSAID class, such as ibuprofen, ketoprofen, naproxen and flurbiprofen. Among the NSAIDs, as among most drugs, one enantiomer of a racemic pair is often more active than the other in treating a medical condition. For ibuprofen, for example, it is the S form which is about 100 times as active as the R as an analgesic.
At present, pharmaceutical companies throughout the world are under pressure from the authorities that regulate drugs to supply all drugs in the pure, active form. The reason for this is that there is always a danger that one enantiomer of a drug may possess the desired activity and the other, although inactive in producing the desired activity, may possess extraneous and even harmful pharmacologic properties. This was most tragically demonstrated in the case of the drug thalidomide in which the S-form was an effective sedative but the R-enantiomer was a teratogen.
Methods for synthesizing or resolving ibuprofen to obtain the pure S enantiomer are known.
Yamamoto et al. [Appl. Env. Microbiol. 56, 3125-3129 (1990)] describe a synthesis of S-ibuprofen (Ia) in 95% enantiomeric excess (ee) from racemic 2-(4'-isobutylphenyl)propionitrile (II) using Acinetobacter. ##STR1##
Cobbs et al. (U.S. Pat. No. 5,108,916) disclose a method for the enantioselective hydrolysis of fenoprofen (III) and ibuprofen (XV) methyl esters to yield the corresponding S-acids in 95% ee using lipase from Candida rugosa. ##STR2##
A similar process is described for naproxen (IV) by Gu et al. [Tet. Lett. 27, 1763-1766 (1986)]. ##STR3##
Bertola et al. (U.S. Pat. No. 5,108,917) disclose a process for the preparation of ibuprofen enriched in the R-isomer from racemic ibuprofen methyl ester using Acetobacter, Bacillus and Staphylococcus.
Bertola et al. (European Application 274,146) disclose the preparation of greater than 70% S-naproxen by the microbially directed oxidation of 2-(6-methoxy-2-naphthyl)heptane(V). Microorganisms that were useful for the oxidation were found in the genera Exophiala and Rhinocladiella: ##STR4##
Matson et al. (U.S. Pat. No. 5,077,217) and Wald et al. (U.S. Pat. No. 5,057,427) disclose a method for the enzymatic resolution of racemic esters in a membrane reactor. Exemplary water soluble esters are described for ibuprofen and naproxen. The preferred enzymes are alkaline proteases, esterases and lipases.
The foregoing methods appear to be useful for obtaining single isomers of phenylpropionic acid NSAIDs, also known as profens, from hydrolysis of nitriles, from hydrolysis of esters of the parent acid and even from .alpha.-oxidation of alkylbenzenes. The method presently used for the commercial production of racemic ibuprofen is described in British Patent 1,160,725 and is shown in scheme A: ##STR5##
It will be noted that nitriles, esters of the parent acid and oxidizable alkylbenzenes do not occur among the intermediates. Thus the use of any of the existing methods to produce a single isomer of a profen entails steps additional to those employed in the production of its racemate.
There is thus a need for a chiral synthesis of ibuprofen that proceeds from an intermediate already available in the normal course of commercial production.
There is also a need for a chiral synthesis of other carboxylic acids that might be synthesized through an aldehyde intermediate.